An MC-4 receptor (melanocortin-4 receptor-specific) agonist metallopeptide will be developed for investigation as a therapeutic agent to modify energy metabolism and feeding behavior, including treatment of pathologic obesity and related conditions. In Phase I, a directed combinatorial library of metallopeptides will be screened against the MC-1 and the MC-4 receptors. The metallopeptide approach was selected based on the discovery by the investigators that a tripeptide sequence can be designed which, when complexed to a metal ion, forms a conformationally restricted structure mimicking a reverse turn characteristic of the melanotropin pharmacophore. These metallopeptides are stable in vivo, with significant resistance to enzymatic degradation. Phase II will include the design of studies to establish metabolic stability and pharmacokinetics, as well as oral viability studies. Phase II will also include direct studies on the efficacy of one or more selected MC-4 receptor agonist metallopeptides in reducing food intake in laboratory animals such as mice, with special focus placed on ascertaining therapeutic efficacy via different routes of administration. PROPOSED COMMERCIAL APPLICATIONS: The anticipated result is a potent, high-affinity and highly selective ligand for the MC-4 receptor which can be developed as a therapeutic agent for treating obesity and related eating disorders and managing energy metabolism.